This application is in response to the RFA (Type C: Research Program for other (non-CNS) solid tumors testing in vivo) to screen agents/combinations against soft tissue sarcoma (Ewing sarcoma, rhabdomyosarcoma, other ST sarcomas) and kidney cancer models (Wilms tumor, rhabdoid). This group has evaluated over 80 agents/combinations using Patient Derived Xenografts (PDX) and cell line derived xenografts as part of the Pediatric Preclinical Testing Program (PPTP). We have developed 12 rhabdomyosarcoma (RMS) PDX models (7 alveolar [ARMS], 5 embryonal [ERMS]), 13 Ewing sarcoma (EWS) models (3 PDX). Additionally, we have 2 alveolar soft part sarcoma models and one each of clear cell sarcoma and undifferentiated sarcoma. In the kidney tumor panel we have developed PDX models representing Wilms tumors (n=8, 2 anaplastic), and 5 non-CNS malignant rhabdoid tumors. Using the xenograft models and SOPs developed in the PPTP, this team has demonstrated capability to provide high-quality, reproducible data evaluating single agents and combinations that have identified entities that have moved rapidly to clinical testing. Specific agents and combinations, identified as having biologically meaningful activity, and in early pediatric clinical trials will be the focus of the hypothesis-driven Aims of the research component: Hypothesis 1: That novel antimitotic agents, eribulin and abraxane will have synergistic interaction with the topoisomerase I poison, irinotecan in sarcoma models. Hypothesis 2. That inhibition of TOR kinase will downregulate the DNA damage repair protein FANCD2 and sensitize sarcomas to ionizing radiation therapy (XRT). Hypothesis 3. Because alveolar soft part sarcomas (ASPS) express very high membrane-associated glycoprotein GPNMB, these tumors will be sensitive to glembatumumab vedotin, an antibody-drug conjugate that targets GPNMB. Further, that glembatumumab will synergize with cediranib, and inhibitor of angiogenesis, and the only identified effective therapeutic for this rare solid tumor. Each study will incorporate pharmacodynamics measures that will inform as to the mechanism of synergy, or failure to synergize as anticipated. Based on outcomes, and results of these PD studies, combinations or sequencing of combinations will be modified. The overall objective is to identify novel combinations that can inform clinical development of these new agents for treatment of childhood solid tumors.
This application is in response to the RFA to screen agents/combinations against soft tissue sarcoma and kidney cancer models. Specific agents and combinations, identified previously by the PPTP as having biologically meaningful activity, and in early pediatric clinical trials will be the focus of the hypothesis-driven Aims of the research component.
|Lowery, Caitlin D; Dowless, Michele; Renschler, Matthew et al. (2018) Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models. Clin Cancer Res :|
|Murphy, Brendan; Yin, Han; Maris, John M et al. (2016) Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis. Cancer Res 76:5798-5809|